The invention relates to a drug patch system based on synthetic rubbers for delivering at least one nonsteroidal antirheumatic for absorption through the skin over a period of up to 24 h, and to a process for producing it.
Transdermal therapeutic systems (TTS) for delivering active substances through the skin have been known for a long time. The topical application of drugs by way of active substance patch systems offers two main advantages. Firstly, this form of administration produces first order release kinetics of the active substance, thereby enabling a constant level of active substance to be maintained in the body over a very long period. Secondly, the path of uptake through the skin avoids the gastrointestinal tract and also the first liver passage. As a result, selected drugs may be effectively administered in a low dose. This is particularly advantageous when the drug is desired to act locally while avoiding a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure sensitive adhesive. In the ready-to-apply product, a pressure sensitively adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing impermeable to the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (klebenanddichten, No. 42, 1998, p. 26 to 30).
A fundamental requirement of a TTS is very good adhesion to skin, which must be maintained over the entire duration of the intended dosing of active substance. A frequently observed side effect, however, is the appearance of skin irritations, which occur in particular when a TTS is applied for a relatively long period, or repeatedly, to the same body region. The principal cause of these irritations are the ingredients of the pressure sensitively adhesive matrix. Painful redetachment of the active substance patch following a prolonged period of wear is a further observation.
Repeated and long-lasting applications of pressure sensitively adhesive systems to the same regions of the human body are encountered above all in the area of ostomy care. In this utility, hydrocolloids have long been used with great success as pressure sensitive adhesives. They consist in principle of a hydrophobic, pressure sensitively adhesive polymer matrix based on synthetic rubbers, dispersed in which matrix there are insoluble hydrophilic fillers based on, for example, alginates, cellulose or pectins. In the development of hydrocolloids for ostomy care, however, the primary requirements are the adhesion properties to wet skin and the ability to absorb liquid.
As long ago as 1967, U.S. Pat. No. 3,339,546 described a hydrocolloid based on polyisobutylenes for use in the oral cavity. A great disadvantage of the early systems was the deficient integrity of the matrices, i.e., the dissolution and breakup of the pressure sensitively adhesive matrix on absorption of relatively large amounts of liquid.
Later developments therefore aimed to solve this problem, and a number of proposed solutions are described in the literature. U.S. Pat. No. 4,393,080, for example, describes a hydrocolloid system based on elastomers, which uses high molecular mass hydrophilic fillers which promote the cohesion of the system even when swollen.
Further patents describe solutions by way of the crosslinking of the elastomer matrix, which may take place either physically or chemically.
Physical crosslinking, for example, may be effected by using phase separating block polymers based on poly(styrene-b-isoprene-b-styrene) (SIS), poly(styrene-b-isoprene-b-styrene) (SBS) or poly[styrene-b-(ethylene-stat.-butylene)-b-styrene] (SEBS). One of the first such systems is described, for example, in DE 28 22 535.
Chemical crosslinking may be effective, for example, by electron beam treatment or xcex3 irradiation of the hydrocolloid matrix. A prerequisite for this is the presence in the pressure sensitively adhesive matrix of a sufficient number of reactive structural elements. This can be achieved, for example, as described in U.S. Pat. No. 4,477,325, by compounding with an ethylene-vinyl acetate copolymer.
Within the abovementioned inventions, although the technical problem of the cohesiveness of swollen hydrocolloids is described and solved, the problem of skin irritation as a result of repeated application is not addressed.
In contrast, WO 98/01167 does deal with skin irritations that may occur. In this case, aloe vera extract is used in order to prevent inflammatory skin changes and infection in the context of ostomy care. The system described, however, merely comprises a low molecular mass polyisobutylene as the polymer framework, and so the above-described problem of the cohesiveness of the hydrocolloid matrix continues to exist. Moreover, the composition described uses tackifier resins, whose allergenic potential is known.
Information regarding the suitability of such a system for the controlled delivery of drugs is present neither in this nor in any other of the abovementioned documents.
Transdermal therapeutic systems are generally applied to healthy, intact skin. In this case in particular it is especially important that the intact skin is not irritated, let alone damaged, by a drug. Furthermore, sufficient cohesiveness is necessary in order to be able to remove the active substance patch without residue after the period of wear is at an end.
Polyisobutylenes have long been used as a framework substance in the compounding of pressure sensitive adhesives. Relative to other known elastomers, synthetic polymers based on isobutylene offer a number of advantages. Owing to their synthetic production, they are free from unwanted ingredients; owing to their complete saturation they are highly stable to oxidation; and their inherent tack can be adjusted depending on molecular weight.
For application to skin in particular, therefore, they are preferred over other elastomers. For example, the allergenic potential of natural rubber, deriving from its natural impurities, is well known. Other synthetic rubbers based on styrene and isoprene and/or butadiene are very oxidation sensitive, necessitating the complicated addition of additives. Their hydrogenated derivatives based on poly[styrene-b-(ethylene-stat-propylene)-b-styrene] (SEPS) or poly[styrene-b-(ethylene-stat-butylene)-b-styrene] (SEBS), although more stable to oxidation, nevertheless lack inherent tack. Because of this, they additionally require compounding with tackifier resins in order to be used as pressure sensitive adhesives, as is described, for example, in EP 0 651 635 B1. These resins are generally very poorly defined mixtures of substances, frequently based on rosin. Consequently, here again an allergenic potential can not be ruled out.
The use of polyisobutylenes for transdermal therapeutic systems was described back in 1983 in DE 33 47 278 and DE 33 47 277. There, however, their use was always described in combination with either olefinic diene rubbers or tackifier resins, which again have the disadvantages described above. The use of amorphous poly-a-olefins as additives is also described, but without elucidating their effect on the overall system. The use of fillers is not mentioned in this description.
The use of PIB for transdermal systems without the addition of tackifier resins is described in U.S. Pat. No. 4,559,222. In that case, however, it is necessary to use very large amounts of mineral oil, the ratio of mineral oil to PIB in accordance with that invention being at least 1. Moreover, the system is restricted to active substances which are of moderate solubility in mineral oil. As a result, there is a further softening effect on the matrix. Fillers used comprise at least 6% by weight of colloidal silica. Regarding this ingredient, it is known that the antiadhesive properties of a release film are significantly disrupted by the use of silica.
WO 96/22083 describes a system for the transdermal administration of nicotine which operates on the basis of polyisobutylene without the addition of mineral oil. In this case, however, the necessary tack of the adhesive composition is achieved through the use of tackifier resins. These have the abovementioned disadvantages with respect to skin compatibility. A plasticizing effect, which has an additional positive effect on the adhesive properties of the matrix, is achieved by way of the active substance which is soluble in the PIB matrix. This compounding principle, however, greatly restricts the selection of active substances which can be administered by way of this matrix.
A system for the transdermal administration of drugs, based on polyisobutylenes without the use either of tackifier resins or of mineral oil, is described by U.S. Pat. No. 5,508,038. The central component for achieving sufficient adhesive properties in this case too, however, is the active substance, which in accordance with that invention must be oily and of ready solubility in the nonpolar matrix. This constitutes a very severe restriction, ruling out the use of nonsteroidal antirheumatics in this context. The system described is free from organic and inorganic fillers.
U.S. Pat. No. 5,508,038 is the only one of the cited publications to address the problem of skin irritation through the possible use of tackifier resins.
The use of amorphous poly-a-olefins in pressure sensitive adhesives in general is known in the literature. U.S. Pat. No. 4,186,258 is one of the first documents which designates the use of this class of substance in the field of hot-melt pressure sensitive adhesives. This document does not state a specific field of use.
U.S. Pat. No. 5,262,216 describes the use of these materials together with tackifier resins as hot-melt pressure sensitive adhesives, specifically for use on self-adhesive labels. Qualities of this class of polymer that are particularly praised here are the outstanding UV and aging resistance. There is no mention of their use on the human body.
WO 98/54268, in contrast, specifically describes the use of amorphous poly-xcex1-olefins for applications on human skin. Moreover, in this case amorphous poly-xcex1-olefins are used in combination with fillers. However, the field of use described is specifically that of wound covering. In this application, a particular feature of amorphous poly-xcex1-olefins is their outstanding radiation resistance, as a result of which, in accordance with that invention, it is possible to produce readily sterilizable woundcare products. Additionally, amorphous poly-xcex1-olefins are used here in combination with tackifier resins. Overall, the aspect of reduced skin irritation is not mentioned. Moreover, WO 98/54268 contains no indications that such a system is suitable for delivering drugs via the human skin. This document completely excludes the field of use of transdermal therapeutic systems.
The systems described to date for the transdermal administration of an active substance do not include organic fillers. However, these fillers in particular are responsible for the kindness to skin of the aforementioned pressure sensitive adhesives for ostomy care. By virtue of these fillers, moisture released by the skin during the period of wear of the patch can be absorbed very effectively. The resulting climate below the patch leads to a marked reduction in the incidence of skin maceration.
An invention of an active substance patch using water swellable fillers is described by EP 0 186 019 A1. In that case, however, the positive influence of the organic filler on the release rate of the active substance is described. The filler content in accordance with that invention is limited to 30% by weight. The aspect of the reduction of skin irritation is not addressed. Moreover, the systems described are realized using tackifier resins.
As remarked above, the realization of pressure sensitive adhesive systems for the transdermal administration of active substances, based on polyisobutyl without either tackifier resins or mineral oil, is described only for those drugs which possess an oily consistency at room temperature and/or which are soluble in the matrix. Consequently, the use of nonsteroidal antirheumatics, such as ibuprofen and ketoprofen, for example, is not possible on the basis of the known formulations, owing to the physical properties of these drugs. None of the tackifier resin free formulations described contains a hydrophilic filler.
It is an object of the present invention to develop, for the purpose of controlled delivery of a drug from the group of the nonsteroidal antirheumatics, a hydrocolloid system which not only possesses excellent cohesiveness but is also composed of components which are particularly kind to the skin and can be realized without any need at all for skin irritant components such as tackifying resins, for example. Furthermore, a production process is planned which operates without any solvent whatsoever, and, furthermore, the abovementioned side effects of a pressure sensitive adhesive for transdermal systemsxe2x80x94skin irritations and painful redetachmentsxe2x80x94are avoided, resulting in a significant increase in wear comfort for the patient.
The object is to provide a matrix system which is based on polyisobutylene and which can be realized in a solvent free production process without conventional tackifier resins and mineral oil.
This object is achieved by an active substance matrix patch as claimed in the main claim. The subclaims relate to advantageous embodiments of the patch of the invention. Furthermore, the invention embraces processes for producing such patches.
The invention accordingly provides an active substance matrix patch for controlled delivery of nonsteroidal antirheumatics to the skin, comprising a flexible cover layer and a water insoluble, pressure sensitively adhesive active substance matrix, said adhesive matrix being free from mineral oils and tackifier resins and being composed of
a) from 25 to 90% by weight of synthetic framework polymers based on polyisobutylene,
b) from 5 to 40% by weight of amorphous poly-a-olefin,
c) from 10 to 60% by weight of an insoluble hydrophilic filler having an average particle size of less than 100 pm, and
d) from 0.001 to 20% by weight of a drug.
In a first advantageous embodiment of the active substance matrix patch, the polyisobutylene is composed of from 5 to 30% by weight of high molecular mass PIB and from 20 to 60% by weight of low molecular mass PIB.
A typical pressure sensitive adhesive of the invention accordingly comprises the following
Optionally, up to 20% by weight of a permeation enhancing auxiliary may also be added.
There follows a more precise definition of the abovementioned formulation constituents:
High molecular mass PIB:
Polyisobutylene having a weight average molecular weight (Mw) of from 500 000 to 1 100 000, preferably between 650 000 and 850 000. Such polymers are available commercially, for example, under the trade name Oppanol B100 (BASF) or Vistanex MM-L80 (Exxon).
Low Molecular Mass PIB:
Polyisobutylene having a weight average molecular weight (Mw) of from 40 000 to 120 000, preferably between 60 000 and 100 000. Such polymers are available commercially, for example, under the trade name Oppanol B15 (BASF) or Vistanex LMMH (Exxon).
Amorphous poly-xcex1-olefin:
Amorphous copolymers based on ethylene and propylene, butylene or 1-hexene. The preferred weight average molecular weight (Mw) is from 5 000 to 100 000, preferably between 10 000 and 30 000. Such polymers are available commercially, for example, under the trade name Eastoflex(copyright) (Eastman) or Vestoplast(copyright) (Hxc3xcls).
Hydrophilic Filler:
Cellulose based hydrophilic particles insoluble in the abovementioned polymer matrix. Preference is given to an average particle size of less than or equal to 100 xcexcm with a surface which is as uniform as possible. Such materials are available commercially, for example, under the trade names Avicel (FMC) and Elcema (Degussa-Hxc3xcls).
The active substance matrix is preferably produced in a process in which all of the components of the pressure sensitively adhesive matrix are homogenized in the melt without the addition of solvent.
With particular preference, all components are processed in a continuous or batchwise process at a temperature below 100xc2x0 C.
The matrix is notable for outstanding adhesion properties on the skin, by easy and painless redetachability, and in particular by its extremely low potential to induce skin irritation. The production process does not use any solvents at all.
If desired, the open adhesive sidexe2x80x94that to be applied to the skinxe2x80x94may be lined with a redetachable, covering protective layer.
As far as the selection of the fillers is concerned, it has surprisingly been found that particularly suitable fillers are those based on cellulose which possess an isotropic form and do not tend to swell on contact with water. Of these, fillers having a particle size of less than or equal to 100 xcexcm are particularly suitable.
The use of hydrophilic fillers in a nonpolar matrix is known in the literature. They are described explicitly for use in transdermal therapeutic systems in EP 0 186 019. In that case, however, they are used only in a concentration of from 3 to 30% by weight, and no details of these fillers are given. Experience shows that systems having a filler content of more than 30% by weight suffer a significant loss of tack and become hard and brittle. In so doing, they lose the fundamental qualities required of a transdermal therapeutic system.
In the context of the present invention, however, it has been possible to show that fillers based on microcrystalline or amorphous cellulose can be used in substantially higher concentrations, without adversely affecting the adhesive properties, when they possess an isotropic form with a particle size of not greater than 100 xcexcm. Larger amounts of fillers are desirable for improving the wear properties, especially in the case of long-lasting and repeated application.
The hydrophilic fillers known from the materials for ostomy care are integrated into the matrix of the invention, which serves to assist in skin compatibility.
The objectivexe2x80x94the topical application of drugs from the group of the nonsteroidal antirheumatics, with or without the assistance of highly skin compatible additivesxe2x80x94may be assisted in the context of the present invention by the addition of permeation enhancing auxiliaries such as, for example, fatty acid esters.
Surprisingly, it is possible to realize the abovementioned requirements in particular by means of a system which besides polyisobutylenes comprises amorphous poly-xcex1-olefins in combination with amorphous or microcrystalline cellulose. The polymer basis of this simple system exclusively comprises synthetic ingredients whose quality can be monitored very effectively. As a result, allergenic reactions can largely be ruled out. The complete absence of poorly defined ingredients such as natural rubber or tackifier resins, for example, leads, as a result, to matrices which are particularly kind to the skin. The adhesive properties of the formulation of the invention, furthermore, can be adjusted very effectively. Moreover, there is no need for additional, stabilizing additives in the system. As already indicated, nonsteroidal antirheumatic topical application systems which are particularly kind to the skin can be realized on the basis of polyisobutylenes using amorphous poly-a-olefins and also cellulose particles as a filler.
The particular advantage of this raw material base lies in the exclusive use of fully saturated synthetic elastomers. These are highly defined and characterized, so making it possible to rule out contamination with accompanying allergenic substances. Because of the high degree of saturation, these polymer are highly stable to oxidation. As a result, there is no need for the extra addition of antioxidants and other stabilizers. The use of such additives, as is necessary when using natural rubber or unsaturated synthetic rubbers, always harbors the danger of skin incompatibility, owing to the chemical structure of the additives most commonly used. In addition, they represent an additional cost factor.
Furthermore, all of the elastomers used possess an inherent tack, depending on the molecular weight. As a result, it is also possible to forego the use of tackifier resins. Tackifier resins are frequently mixtures of substances, prepared on the basis of rosin, which are very poorly defined. A uniform structural formula can be given only in the rarest of cases. This makes it difficult to use tackifier resins as raw materials in drugs requiring approval, as in the present case of the transdermal therapeutic systems.
Because of the molecular weight dependent adhesion capacity on skin both of the polyisobutylenes and of the amorphous poly-a-olefins, the adhesive properties of the system of the invention may be adjusted within a very wide range without having to alter the chemistry of the base components. Often, a slight variation in the percentage proportions of the basic components is enough to give desired product properties.
This aspect is very important especially within drug development. The careful selection of unobjectionable raw materials possessing good skin compatibility is costly and time consuming. It is therefore desirable to be able to make specific adjustments to product properties by varying the percentage composition of the known raw materials, thereby obviating the time consuming replacement of a complete raw material.